Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of a synthetic peptide, corresponding to a sequence of HIV-1 p24 protein (amino acids 218-237), on in vitro immune responses was studied. The peptide inhibited in a dose-dependent manner the induction of an anti-SRC antibody response and of a PPD-specific proliferative response of human PBL. On the other hand, PHA-induced proliferation of human PBL and PPD-induced proliferation of a PPD-specific human T-cell line were not modified by comparable amounts of the peptide. These results suggest that structures from a protein (p24), present in the serum throughout the course of HIV infection, are able to interfere with the inductive stages of specific immune responses. These findings may help to unravel some of the pathogenic mechanisms of AIDS and may contribute to the development of vaccine strategies.
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PMID:Immunoregulatory effect of a synthetic peptide corresponding to a region of protein p24 of HIV. 211 80

Autoreactive lymphocytotoxic antibodies, which have been found in sensitised dialysis patients, are generally not considered to be harmful to a renal allograft. In this work the presence of such autoreactive antibodies was investigated in the following groups of sensitised endstage renal disease patients: (a) dialysis patients waiting for a first kidney transplant, (b) kidney transplanted patients, and (c) dialysis patients with a previous failed graft. Only sera from the above patients which showed high reactivity (greater than 30%) against peripheral blood lymphocytes of a random cell panel (R-PBL), were screened for the presence of autoreactive lymphocytotoxic antibodies, by testing at different temperatures against autologous T lymphoblasts (PHA-ATL) and EBV-induced autologous B lymphoblasts (EBV-ABL). The results showed that both blood transfusions, and viral infections such as cytomegalovirus (CMV), correlated with the presence of autoreactive antibodies, and that in addition, by using PHA-ATL and/or EBV-ABL as absorbing reagents, it was possible to remove the antibodies. These absorption procedures allowed the identification of the presence of autoreactive antibodies alone or in combination with other alloantibodies.
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PMID:Identification of autoreactive lymphocytotoxic antibodies in sensitised dialysis and kidney transplant patients. 282 88

The purpose of this study was to evaluate the effect of increased arginine levels in intravenous hyperalimentation (IVH) therapy on wound healing and thymic immune function. Groups of SD rats, 275-325 g, underwent placement of internal jugular catheter, 7-cm dorsal skin wounding, insertion of polyvinyl alcohol sponges subcutaneously, and closure of wounds with stainless-steel sutures. Twenty-four hours later, rats were started on IVH at a rate of 0.8-1 ml/100 g body wt/hr. All IVH solutions contained 20% dextrose, adequate amounts of minerals and vitamins, and two different amino acid mixtures: (A) Fre III (4.05 g ARG/liter) (n = 13); (B) experimental (7.50 g ARG/liter) (n = 11). Solutions were isonitrogenous, and contained similar amounts of essential amino acids. After 7 days of IVH, weight gain did not differ between the two groups; however, cumulative N balance was superior in group A. Wound healing was improved in group B as assessed by fresh wound strip breaking strength, fixed breaking strength, and the amount of reparative collagen deposition as assessed by the hydroxyproline content of the implanted sponges. Group B animals also had improved thymic function as assessed by thymic weight, the total number of thymic lymphocytes/gland and mitogenic reactivity of thymic lymphocytes to PHA and Con A. The experiments indicate that high arginine levels in IVH solutions improve wound healing and thymic immune function following injury.
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PMID:Intravenous hyperalimentation with high arginine levels improves wound healing and immune function. 392 66

Trauma victims often suffer immune system failure. Oral arginine has strong immune-enhancing properties. The metabolic, hormonal, and immune effects of increasing concentrations of arginine as part of post-trauma intravenous hyperalimentation (IVH) were studied. Groups of 11-14 rats, 275-350 g, underwent jugular vein catheterization and bilateral closed femoral fractures under anesthesia. IVH was started immediately postinjury at a rate of 0.8-1 ml/100 g body wt/hr and continued for 5 days. Twenty percent dextrose and three different amino acid mixtures were given as follows: (A) FreII (1.55 g ARG/1); (B) FreIII (4.05 g ARG/1); (C) modified FreIII (7.9 g ARG/1). All rats lost weight over the 5-day postinjury period; however, rats in groups B and C lost significantly less weight than rats in group A (-3.4 +/- 0.8% of initial body weight and -3.6 +/- 0.9% vs -6.1 +/- 1.2%, P less than 0.05). Rats in group A had negative cumulative nitrogen balance, while those in groups B and C were in highly positive balance. No significant difference in body weight change or nitrogen balance was noted between groups B and C. Trauma-induced thymic involution as assessed by thymic weight and lymphocyte content was greatest in group A, which received the lowest amount of arginine, and was linearly abrogated by increasing the amount of arginine administered (A less than B less than C). Thymocyte immune responsiveness increased with the amount of arginine given as assessed by mitogenesis in response to Con A (stimulation index: A--151.3 +/- 28.8 vs B--243.6 +/- 29.2, P less than 0.01 vs C--321.8 +/- 22.3, P less than 0.001 vs A and P less than 0.02 vs B) and PHA (A--65.0 +/- 14.3 vs B--67.7 +/- 15.3, NS, vs C--117 +/- 14.0, P less than 0.005 vs A and B).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:High arginine levels in intravenous hyperalimentation abrogate post-traumatic immune suppression. 642 25

IL-12 is a novel heterodimeric cytokine important for the regulation and differentiation of lymphocytes and NK cells. Like other cytokines, IL-12 mediates its biologic activity through high-affinity receptors expressed on responsive cells. To date, a large number of receptors for IL-12 have been found only on PBMC following activation with PHA or IL-2. To gain further knowledge of the IL-12R complex and the IL-12 signal transduction pathway in cytotoxic T cells, we studied a number of human T cell lines that had been transformed to permanent growth with Herpesvirus saimiri, an oncogenic virus of nonhuman primates. This paper reports the expression of IL-12R on a human gamma delta T cell line that responds to IL-12 with enhanced cytolytic activity and increased expression of cytolytic effector molecules granzyme B and perforin. Using these T cells as a model of IL-12 signal transduction, we confirmed that these events involve members of the Janus kinase family of nonreceptor tyrosine kinases JAK2, TYK2, and signal transducer and activator of transcription 4.
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PMID:Herpesvirus saimiri immortalized gamma delta T cell line activated by IL-12. 860 93

The BCR/ABL fusion protein transforms myeloid stem cells. Both chronic myelogenous leukemias (CML) and a subset of acute lymphoblastic leukemias (ALL) are associated with the expression of BCR/ABL proteins. This knowledge has not yet been translated into any specific tool to control ABL driven neoplastic cells growth. CGP57148B is an ATP-competitive inhibitor of the ABL protein kinase; it has been shown to inhibit the kinase activity of ABL both in vitro and in vivo and to inhibit the growth of v-abl and bcr/abl transfectants, as well as the in vitro formation of bone marrow (BM)-derived colonies in the presence of growth factors in some CML patients. These studies were performed to investigate the activity of CGP57148B on the spontaneous proliferation of both fresh and cultured, leukemic and normal, BCR/ABL positive and negative cells, and to study its mechanism of action. Six cell lines derived from BCR/ABL+ leukemias (K562, BV173, KCL22, KU812, MC3, LAMA84), thirteen BCR/ABL negative lines, both neoplastic (KG1, SU-DHL-1, U937, Daudi, NB4, NB4.306) and derived from normal cells (PHA blasts, LAK, fibroblasts, LCL, renal epithelial cells, endothelial cells, CD34(+) cells), and 14 fresh leukemic samples were tested using a tritiated thymidine uptake assay. The in vivo phosphorylation of the BCR/ABL protein was evaluated by western blot, while apoptosis was detected by the annexin V/propidium binding test. The induction of differentiation was assayed by immunofluorescence using multiple antibodies. All six BCR/ABL+ lines showed a dose dependent inhibition of their spontaneous proliferative rate, which was not accompanied by differentiation. The treatment caused, within minutes, dephosphorylation of the BCR/ABL protein, followed in 16-24 hours by a decrease in cycling cells and induction of apoptosis. No significant inhibition of DNA synthesis was observed in any BCR/ABL negative normal or neoplastic line at concentrations </=3 microM, with the exception of fibroblasts and CD34 cells. Proliferation inhibition was observed also when using fresh samples obtained from two Ph+ ALL and 12 consecutive CML patients. Induction of apoptosis was observed in these samples too. The activity of CGP57148B can be monitored in ex vivo isolated or cultured cells using a simple and reproducible assay, without the need for exogenously added growth factors. This molecule possibly exerts its effects through the inhibition of the kinase activity of BCR/ABL and the subsequent initiation of apoptosis, without inducing cell differentiation. Some normal cells are also affected. These data support the use of CGP57148B in initial clinical studies; possible toxic effects on BM and fibroblast-derived cells will have to be closely monitored. The in vivo monitoring of patients will have to be focused on the induction of apoptosis in leukemic cells.
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PMID:Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis. 944 52

IL-13, a cytokine similar to IL-4, is a regulator of human B cell and monocyte functions. Biologic effects of IL-13 on primary human NK and T cells have not been well defined. We demonstrate that, in primary NK cells, IL-13, but not IL-4, may induce low levels of IFN-gamma secretion. When NK cells were costimulated with IL-13 and IL-2, IL-13 generally resulted in two types of reactivity: IL-13 synergized with IL-2 to stimulate IFN-gamma production or it modestly inhibited IL-2-mediated IFN-gamma production. In both types of donors, the effect of IL-13 on IL-2-induced IFN-gamma production was in marked contrast to the strong inhibition seen with IL-4 in NK cells. Additionally, IL-13 suppresses IL-2-induced NK cytolytic and proliferative activities although less efficiently than IL-4. In T cells, IL-13 inhibits anti-CD3 mAb/IL-2- or PHA-mediated IFN-gamma production and enhances cytolytic potential. Furthermore, we demonstrate that IL-13, like IL-4, induces distinct STAT6-DNA binding complexes and tyrosine phosphorylation of STAT6 and Janus kinase 3 (JAK3) in NK and T cells. We observed that Abs directed against unique domains of STAT6 have differential effects on complexes in T cells but not in NK cells, suggesting different STAT6 isoforms. These findings show that IL-13 and IL-4 have the ability to regulate NK and T cell activation and that IL-13 is a potent regulator of STAT6 and JAK3 in these cell types.
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PMID:Differential regulation of the Janus kinase-STAT pathway and biologic function of IL-13 in primary human NK and T cells: a comparative study with IL-4. 964 27

Clonal del(22q) chromosome aberrations were coincidentally observed in highly exposed reactor personnel of the Chernobyl power plant accident in the course of retrospective biological dosimetry. These aberrant chromosomes were detected in PHA-stimulated cultures from peripheral blood after FPG staining and revealed a morphology similar to a Philadelphia chromosome. A rearrangement of the BCR gene on 22q11 could be confirmed in unstimulated peripheral blood by RFLP analysis from three of four del(22q) carrying cases. FISH analysis of the del(22q) carrying cases with BCR- and ABL-specific DNA probes additionally exhibited a BCR-ABL fusion in 5.2 to 9% of cells in unstimulated blood. Breakpoints within the BCR gene could be located either in the M-bcr or the m-bcr region and thus, a specific breakpoint region could not be detected in these four patients. Since typical clinical leukemic symptoms associated with the translocation (9;22)(q24;q11) could not be observed in these highly irradiated subjects (1.1 to 5.8 Gy), the role of this particular aberration in the development of a radiation-induced leukemia remains obscure.
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PMID:Molecular genetic characterization of the Philadelphia chromosome detected in reactor personnel highly exposed to radiation from the Chernobyl accident. 966 99

"LETRA S. SIDA. Cultura y Vida Cotidiana" is a monthly 16-page supplement that appears in the Mexican national newspaper "La Jornada." The supplement is produced by a nongovernmental organization (NGO) of the same name, and advertisements pay for the costs of production. Each issue studies a different AIDS theme, including women, indigenous people, migration, safe sex, homophobia, religion, and education. Each theme is approached from various perspectives, including epidemiology, medicine, sexuality, human rights, social science research, culture, and the arts. Populations most at risk are targeted. The aim is to arouse cultural criticism of taboos, prejudice and discrimination, sexual inequality, and gender issues that facilitate the transmission of HIV. Official health policies and the activities of groups, conservative and religious, which reject prevention programs are scrutinized. Each issue of the supplement includes a journalistic investigation providing statistics, facts, and opinions; interviews with health and education officials, politicians, state governors, and NGO staff; background articles by intellectuals, researchers, and well-known persons in Mexican society; PHA testimonies; reports on research and conferences; letters to the editor; cultural reviews relating to the theme of the issue; and a directory of NGOs doing HIV/AIDS work and of health institutions serving PHAs. The supplement has gone from a print run of 25,000 copies, when it was published as part of "El Nacional" (another government newspaper), to 70,000 in "La Jornada." The NGO has recently won the "Francisco Estrada Valle" award for its work.
AIDS STD Health Promot Exch 1996
PMID:Country watch: Mexico. 1234 32

The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the development and progression of several human cancers and are attractive targets for cancer therapy. PHA-665752 was identified as a small molecule, ATP-competitive, active-site inhibitor of the catalytic activity of c-Met kinase (K(i) 4 nM). PHA-665752 also exhibited >50-fold selectivity for c-Met compared with a panel of diverse tyrosine and serine-threonine kinases. In cellular studies, PHA-665752 potently inhibited HGF-stimulated and constitutive c-Met phosphorylation, as well as HGF and c-Met-driven phenotypes such as cell growth (proliferation and survival), cell motility, invasion, and/or morphology of a variety of tumor cells. In addition, PHA-665752 inhibited HGF-stimulated or constitutive phosphorylation of mediators of downstream signal transduction of c-Met, including Gab-1, extracellular regulated kinase, Akt, signal transducer and activator of transcription 3, phospholipase C gamma, and focal adhesion kinase, in multiple tumor cell lines in a pattern correlating to the phenotypic response of a given tumor cell. In in vivo studies, a single dose of PHA-665752 inhibited c-Met phosphorylation in tumor xenografts for up to 12 h. Inhibition of c-Met phosphorylation was associated with dose-dependent tumor growth inhibition/growth delay over a repeated administration schedule at well-tolerated doses. Interestingly, potent cytoreductive activity was demonstrated in a gastric carcinoma xenograft model. Collectively, these results demonstrate the feasibility of selectively targeting c-Met with ATP-competitive small-molecules and suggest the therapeutic potential of targeting c-Met in human cancers.
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PMID:A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. 1461 33


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